Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder of immune dysregulation associated with uncontrolled T cell and macrophage activation and hypercytokinaemia. The incidence of FHL is 0.12/100.000 children born per year, with a male to female ratio of 1:1. The disease is classified into six different types based on genetic linkage analysis and chromosomal localization; five specific genetic defects have been identified, which account for approximately 90% of all patients. Type 1 is due to an as yet unidentified gene defect located on chromosome nine. Type 2 is caused by mutations in the perforin (PRF1) gene, type 3 by mutations in the Munc-13-4 (UNC13D) gene, type 4 by mutations in the syntaxin 11 (STX11) gene and the recently described type 5 due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2). The incidence of the five types varies in different ethnic groups. The most common presenting features are pyrexia of unknown origin, pronounced hepatosplenomegaly and cytopenias. Neurological features tend to present later and are associated with poor prognosis. Absent or decreased lymphocyte cytotoxicity is the cellular hallmark of FHL. Biochemical features such as hyperferritinaemia, hypertriglyceridaemia and hypofibrinogenaemia are usually present, along with high levels of soluble interleukin 2 receptor in the blood and cerebrospinal fluid. Bone marrow aspirate may demonstrate the characteristic haemophagocytes, but initially is non-diagnostic in two-thirds of patients. Established international clinical, haematological and biochemical criteria now facilitate accurate clinical diagnosis. The disease is fatal unless a haematopoietic stem cell transplant (HSCT) is performed. The introduction of HSCT has dramatically improved the prognosis of the disease. However, the mortality of the disease is still significantly high and a number of challenges remain to be addressed. Active disease at the time of the transplant is the major significant poor prognostic factor. Delayed diagnosis, after irreversible organ damage has occurred, especially neurological damage, disease reoccurrence and pre-transplant mortality, remain a concern.